ALTERED EXPRESSION OF TITIN AND CONTRACTILE PROTEINS IN FAILING HUMANMYOCARDIUM

Our own previous ultrastructural studies in human hearts with dilated cardiomyopathy and heart failure showed sarcomeric and cytoskeletal di sarrangement. On the basis of these findings we tested the hypothesis that in cardiomyopathic failing hearts not only the sarcomere structur e but also the organization and the amount of numerous contractile pro teins are disturbed, Titin was included in this study because it is th e elastic ''third'' filament of the sarcomere and also plays an import ant role as template for myosin and actin filaments in sarcomerogenesi s. Human cardiac tissue obtained at the time of transplantation surger y was investigated using immunohistochemistry with monoclonal antibodi es against titin, myosin, actin, tropomyosin, and troponin T. Addition ally, isolated myocytes from rat or pig heart were used for the standa rdization of the localization pattern. In normal tissue, myosin and th e thin filament complex showed a regular cross striation that was wide r in myosin staining than for actin, troponin T, and tropomyosin corre sponding with the different width of the A and I bands in the sarcomer e. Titin localization in normal human and animal myocardium showed a r egular cross striation pattern. In diseased cardiac tissue titin fluor escence intensity was reduced and frequently disorganization or almost complete loss of titin from many myocytes were present. Severe abnorm alities of contractile proteins consisting of disarrangement or lack o f filaments were also observed. Double staining procedures showed that in the same myocyte defects of the contractile apparatus were accompa nied by a simultaneous reduction of titin indicating that the ''third' ' sarcomeric filament system is involved in heart failure. Abnormaliti es of titin expression may be especially important because titin signi ficantly influences sarcomeric elastic behaviour and is necessary as t emplate for the organization of newly synthesized myosin and actin fil aments. The loss of titin may contribute to the altered compliance in failing hearts. It is concluded that disorganization and loss of titin , myosin, and the thin filament complex are severe in the failing huma n heart because of dilated cardiomyopathy and that these changes may r epresent several of the most important components of the structural co rrelate of reduced cardiac function.